Int J Evid Based Healthc 2013; 11: 330–336


Thought for food: Clinical evidence for the dietary prevention strategy in cardiovascular disease Barry Lewis MD PhD FRCP (London) FRCPath,1 David R Sullivan MD FRACP FRCPA2 and Gerald F Watts DSc MD PhD FRACP3 1

University of London, London, UK; 2Department of Clinical Biochemistry, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, and 3Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia

Abstract A modified diet has been advocated for the past 50 years for prevention of cardiovascular disease. The evidence has in the past been largely epidemiological and experimental, with relatively limited support from clinical trials. However a major element of this strategy, reduction in intake of saturated fats, has recently been called into question; the evidence for and against this view is critically reviewed. A Cochrane review, and recent trials, have advanced our understanding of the role of diet and of optimal dietary recommendation strategy. Here we consider these advances in the light of established knowledge.

Key words: cardiovascular disease, dietary recommendation, low-density lipoprotein cholesterol, Mediterranean diet, prevention.

Introduction Despite four decades of impressive progress in the prevention and treatment of cardiovascular diseases (CVDs), these disorders remain the commonest cause of adult death worldwide.1 Clinical trials have contributed in differing degree to prevention strategy: a wealth of trials has established the effectiveness of primary and secondary prevention of CVD by drug treatment to reduce blood levels of lowdensity lipoprotein cholesterol2,3 and to lower elevated blood pressure. By contrast, the undoubted value of antismoking measures is, and is likely to remain, unsupported by large-scale unifactorial controlled trials; one relatively small trial has reported non-significant reductions in coronary heart disease (CHD) of 18% at 10 years and 13% at 20 years.4 The large-scale Multiple Risk Factor Intervention Trial however reported that a major reduction in CHD mortality was attributable to smoking cessation.5 Recent trials, and a Cochrane Review,6 have enhanced our understanding of the role of population-wide dietary recommendations for reduction of CVD.

Correspondence: Barry Lewis, Emeritus Professor, University of London, London, UK. Email: [email protected]

The evidence for dietary recommendations Dietary recommendations have been one of the central elements of preventive strategy for 50 years.7 They were based initially on consistent, powerful epidemiological studies showing the predictive power of serum cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apoB) levels for cardiovascular disease (CVD) events. Earlier epidemiological work employed international cohort studies and reported that coronary heart disease (CHD) mortality was correlated with and predicted by intake of saturated fat for CHD mortality (the Seven Countries Study8). An international study of coronary atherosclerosis (International Atherosclerosis Project)9 similarly showed the ranking of the extent of arterial disease to correspond with the ranking of serum cholesterol and with consumption of saturated fat in the several participating countries. Consistent with the epidemiology, feeding experiments in laboratory animals10 showed that atherosclerosis could be induced by high-cholesterol diets and caused to regress by cholesterol lowering.11 The validity of the Seven Countries Study has been called into question.12 The Cochrane Review6 cites two recent studies reporting contrary findings. One, a systematic review,13 included a meta-analysis of within-population cohort studies. This failed to detect a significant relationship

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between the intake of saturated, mono-unsaturated and poly-unsaturated fatty acids and the incidence of CVD; only trans-unsaturated fatty acids (directly) and fish intake (inversely) were related to CVD. However, the authors did not regard their findings as negating the Seven Countries Study; in their discussion, they argued instead that the null results were likely to reflect the limitations of the methods used for dietary assessment in the studies reviewed, and regression dilution bias. The other review14 described a further meta-analysis of 21 within-population cohort studies and found no evidence that intake of saturated fat is associated with the incidence of CVD or CHD. The latter paper has in turn been the subject of a point-by-point rebuttal.15 The range of saturated fat intake in cross-cultural studies is wider than in within-population studies, giving the former a greater likelihood of detecting a relationship with CVD rates. Further, the methods for assessment of dietary intake of saturated fat differ substantially between these types of investigation. The within-population studies have mostly employed questionnaires or dietary records to estimate nutrient intake. The Seven Countries Study, on the other hand, recorded the weights of foods consumed over a 7-day period and used region-specific food composition tables; findings were validated in a subsample by duplicate food analyses.16,17 The methods used in the Seven Countries Study must be presumed to have yielded more robust data, giving its observations greater validity. Among its many contributions, the Seven Countries Study drew attention to the inverse association between the Mediterranean diet, as consumed in three of its cohorts in the 1950s (when the data were recorded) and mortality from CHD. A meta-analysis of nine cohort studies18 has since reported a graded inverse relationship between adherence to this diet and both CVD mortality and all-causes mortality. In a large Greek cohort,19 more detailed analysis of the components of the Mediterranean diet was performed. There were several contributing elements: low intake of meat, high consumption of vegetables, fruit, nuts and fish, and moderate intake of alcohol. In conformity with this, an institutional feeding experiment has shown that a high intake of vegetable and fruit has an additive effect with that of a low-fat, fat-modified diet in substantially reducing LDL cholesterol.20

Determinants of serum cholesterol levels within and between populations There is no doubt that serum cholesterol and LDL cholesterol levels are directly and strongly related to CVD and CHD risk,21 and because of their size and power, trials of statins show that the relation between LDL reduction and CVD event reduction is congruent with this epidemiology.3,22 It is also beyond doubt that the type and amount of dietary fat have substantial effects on serum cholesterol and LDL cholesterol levels.23,24 The correlations observed in cross-cultural studies such as the Seven Countries Study are clearly environmental: for a study of acculturation of Japanese men who


migrated to Hawaii and California25 has established how rapidly their mean serum cholesterol and CHD rates approximated to those of the host country. However, there is a contrast between the strong correlations demonstrable between dietary fat intake and mean serum cholesterol level in international (cross-cultural) epidemiological studies and, conversely, the difficulty in establishing such correlations in within-population studies. A plausible interpretation is that dietary differences are major determinants of the wide variation between populations in mean serum cholesterol and in CHD mortality; the dietary pattern typical of high-CHD populations includes a high intake of dietary energy, saturated fat and refined carbohydrate. There has been considerable convergence of diets in high- and low-CHD countries as the original observations were made by Keys8 and McGill9 some 60 years ago. The Food and Agriculture Organization data show that per capita intake of animal fats in Japan was 13.8 g/day in 1961, increasing to 34.5 g/day in 2009; in Finland, intake fell from 102 to 93.7 g/day in the same period.26 A corresponding rise in CHD mortality in this country was observed during the post-war period.27 By contrast, the role of diet within single populations may be to set a population mean serum cholesterol, around which other factors are the main determinants of individual variation. One such intra-population variable is likely to be body weight. Further, there is now a considerable body of evidence of genetic factors influencing plasma lipid metabolism (over and above the major monogenic hyperlipidaemias related to genes of large effect). This evidence in turn falls into two groups. The first comprises the several lowpenetrance genetic polymorphisms that are associated with differences in mean serum cholesterol and other lipids. The second includes a number of studies demonstrating genetic influences on the magnitude of individual variation in the plasma lipid response to dietary intervention. The first category has been studied extensively in the past 20 years. In a Jerusalem lipid clinic population, heritability of variation in LDL cholesterol levels was estimated to be 0.45 and that of HDL cholesterol 0.47.28 An Australian study on 415 pairs of apparently healthy monozygotic and dizygotic twins yielded similar estimates: genetic variation contributed up to 45% of differences in LDL cholesterol and up to 48% of variation in HDL cholesterol.29 More recently, genomewide association studies on about 20 000 subjects in different European countries have identified 22 loci influencing levels of LDL cholesterol, HDL cholesterol and triglyceride: genes in these loci code for several determinants of lipid metabolism, inter alia apolipoprotein B, the LDL receptor, PCSK9, HMGCoA reductase, lipoprotein lipase and the ABCA1 transporter.30 In the second category, a study on 302 pairs of twins reared together or apart31 has described a substantial genetic contribution to variation in the response of plasma levels of lipids, lipoproteins and apolipoproteins to dietary change; heritability ranged from 0.28 to 0.78. In this study, the heritability of environmental factors during the rearing period was 0.15–0.36. A systematic review of the genetics

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of dietary responsiveness32 covers an extensive literature; polymorphism of genes coding for apolipoprotein B has a large effect, and evidence is reviewed for the effect of polymorphisms for genes coding for apolipoprotein E, for the apo A-I, C-III, A-IV cluster, lipoprotein lipase and the LDL receptor. The authors interpret these findings cautiously, on the grounds that the studies have mostly been small, and that there are some inconsistencies. It may be concluded that dietary pattern is the substantial determinant of differences in mean lipid levels between populations, whereas genetic factors and gene-diet interactions appear to be largely responsible for individual differences in lipid and lipoprotein levels.

ground of high rates of smoking, the prevalence of which has since fallen.38 In its place, obesity and insulin resistance have become increasingly common.39 The role of lipoprotein metabolism in the aetiology of atherosclerotic CVD differs between these two sets of circumstances. Formerly, elevated levels of LDL and increased oxidation of LDL40 are likely to have predominated; obesity on the other hand is associated with adverse changes in the composition of cholesteroltransporting lipoproteins (reduced levels of HDL cholesterol and cholesterol depletion of LDL to form small, dense, more atherogenic lipoproteins).41

First generation clinical trials

Further clinical trials of dietary and other interventions have employed coronary angiographic end points.42 One was a 1-year trial of multiple interventions including a stringent diet;43 regression of atherosclerotic lesions was noted. In another trial of a 3-year duration by Watts et al.,44 we employed a lipid-lowering diet as the single intervention in one intervention group; progression of coronary lesions was arrested in this group. In this trial, the diet, based on earlier feeding experiments,20 comprised reduction of saturated fat and cholesterol, a moderate supplement of omega-6 polyunsaturated oil, and increased intake of fruit, vegetables and dietary fibre. A substantial 16% reduction of LDL cholesterol was achieved throughout the study. The most evident nutritional correlation was between atherosclerosis progression and intake of saturated fatty acids,45 whereas omega-6 poly-unsaturated fatty acid intake showed no significant relationship. Using carotid intima-medial thickness as an end point, a trial of weight loss together with either a low-fat, a low-carbohydrate or a Mediterranean dietary pattern reported decreased intima-medial thickness with all three interventions.46

The status of clinical trials of dietary lowering of plasma cholesterol deserves further consideration. Such trials, for most of the past half century, had not provided as definitive a body of evidence as one would wish to validate a policy of making public dietary recommendations; as with antismoking guidance, epidemiology has hitherto been the main foundation for dietary recommendations. The earliest, very underpowered trials, achieving only limited cholesterol lowering, yielded inconsistent results, though as trial design improved, evidence of benefit accumulated.33,34 One very large primary prevention trial of multifactorial intervention, including diet, reported a small reduction in risk factor levels and in CVD events.35,36 Another trial of a carefully supervised diet together with anti-smoking counselling37 yielded substantial reduction in primary events; retrospective analysis suggested that diet contributed significantly to this reduction. A meta-analysis of unifactorial dietary trials up to 1994 confirmed modest benefit.2 In most of these trials, the dietary intervention comprised reduction in intake of saturated fat and its replacement to a varying extent by oils and fats with a high content of linoleic acid (i.e. the ‘fat-modified diet’).

Cochrane Review of clinical trials A recent Cochrane Review selected 48 clinical trials of the effect of reduced-fat or fat-modified diets on CVD.6 There was a significant 14% reduction in CVD events but no significant effects on neither total mortality nor CVD mortality. Among the trials, those studying a fat-modified diet were found to achieve a modest mean reduction of serum cholesterol of 0.44 mmol/L, whereas those studying total fat reduction together with fat modification achieved a reduction of 0.21 mmol/L. In large-scale dietary trials, it is notoriously difficult to achieve and to maintain close compliance over several years and hence to reduce serum cholesterol substantially; it is therefore plausible that the modest lessening of CVD rates observed in the Cochrane Review reflected the small extent of the reductions of serum and LDL cholesterol in these trials. Furthermore, the background pattern of other CVD risk factors has changed over time. Early epidemiological and dietary intervention studies were performed against a back-

Atherosclerosis imaging trials

Changing dietary recommendations The composition of cholesterol-lowering diets recommended to the public and used in clinical practice has changed considerably over time. Reduction in saturated fat intake remains the central feature. Initially, an increased intake of linoleic acid-rich foods was introduced on the basis that feeding experiments showed its serum-cholesterol-lowering effect as reflected in the formulae of Keys8 and of Hegsted et al.;47 these formulae indicated that the extent of this lowering effect was about half of the cholesterol-elevating effect of saturated fats. A meta-analysis of 60 nutritional experiments48 affirmed that when carbohydrate was replaced isocalorically by saturated fatty acids, LDL cholesterol increased; it was increased to a greater extent by transunsaturated fatty acids; it was decreased by substitution of poly-unsaturated fatty acids (excluding those of marine origin) and decreased to a lesser extent by mono-unsaturated fatty acids. However, the use of high linoleic acid diets has since been de-emphasised and replaced by foods providing oleic acid, and omega-3 fatty acids of marine and plant origin, together with substantially increased intake of vegetables,

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fruit and soluble fibre-rich cereal; control of dietary energy to achieve ideal body weight has become an essential feature. Until recently, the evidence for this latter regime has been derived from epidemiology, in particular the relationship between the ‘Mediterranean’ diet and CVD mortality7,23 and from extensive study of potential mechanisms. For example, olive oil is less subject to oxidative damage during cooking than linoleate-rich seed oils,49 whereas LDL from subjects fed diets high in oleic acid is similarly less prone to oxidation than is LDL from linoleate-fed subjects;50 modification of LDL (e.g. by oxidation or glycation) permits its uptake by arterial wall macrophages, so promoting atherogenesis.40 Foods of plant origin have an LDL-cholesterol lowering effect additive to that because of changes in dietary fatty acid composition20,51 and plant sterol content.52 Antioxidants provided by plant-derived foods are regarded as protective, inter alia, against LDL oxidation.53 The consumption of seed oils as ‘poly-unsaturated’ margarine has, in the past at least, been accompanied by intake of trans-unsaturated fatty acids produced during partial hydrogenation; such fatty acids, like saturated fats, elevate LDL cholesterol levels48 and are associated with increased CVD risk.54 The prostaglandins and thromboxanes derived from omega-3 unsaturated fatty acids inhibit platelet aggregation to a greater extent than omega-6 fatty acids such as linoleic acid.55 Apart from their influence on plasma lipids, dietary fats have several effects of possible relevance to CVD risk. These include influences on inflammatory markers and endothelial function.56 Dietary fats also have well-documented effects on insulin sensitivity, lipoprotein oxidation and arterial stiffness. These reviews suggest that further studies are required to establish to what extent these relationships have causal significance. The role of the type of dietary carbohydrate in CVD was a subject of controversy in the past. The risk of myocardial infarction is directly related to consumption of carbohydrate with high glycaemic index (GI) but is not significantly related to intake of low GI carbohydrates.57 In the context of a rising prevalence of obesity and type 2 diabetes, the adverse effects of a high intake of high GI foods assume even greater significance.

Trials of the ‘Mediterranean’ diet In 1999, the final results of a trial was reported of a Mediterranean diet (i.e. comprising low saturated fat, increased intake of olive oil, of fruit, vegetables, nuts and fish, and of fat rich in the omega-3-unsaturated fatty acid alpha-linolenic acid).58,59 The end point was incidence of CVD, which showed substantial reduction in the number of events. This was a secondary prevention trial of 46 months duration and provided the first trial evidence of benefit from this dietary regime. Recently, a dietary primary prevention trial on 7447 subjects at increased CVD risk has been reported, the Predimed Trial.60 It considerably advances the body of evidence that a change in diet can reduce CVD event rates in subjects without


evidence of CVD. There were two intervention groups, both receiving versions of the Mediterranean diet; in one, participants were asked to consume 50 g/day of an extra-virgin olive oil with a high content of polyphenol antioxidants, whereas the other group received 30 g/day of almonds, walnuts and hazel nuts. Both intervention groups were required to reduce sources of saturated fat and to supplement the diet with fruit, vegetables, oily fish, legumes and cereals. The control group was instructed to follow a low-fat diet. There was a composite end point of myocardial infarction, stroke and death from cardiovascular causes. Dietary compliance was partial; analyses were on an intention-to-treat basis. Because of favourable trends in the intervention groups, the trial was terminated after a mean of 4.8 years instead of the intended 6 years. There were 96 events in the olive oil group, 83 in the group receiving nuts and 109 in the controls. In both intervention groups, there were significant 30% reductions in relative risk of CVD events. Total mortality showed a non-significant trend to a reduced rate in the olive oil group. Both stroke and myocardial infarction rates decreased, the former significantly. The number of events was admittedly small by comparison with recent statin trials, and double blinding is not achievable in a dietary trial. A limitation of trial execution was the lesser compliance with the low-fat diet in the control group during the first few years. The study is of importance in demonstrating that it is feasible to obtain reasonably good compliance in large-scale dietary trials; it is plausible that Predimed represents the best that can be achieved in such a trial. Predimed therefore represents a remarkable advance. The authors regarded increased consumption of olive oil and nuts as the probable effective components of the Mediterranean diets employed. Inclusion of omega-6-rich oils in a recommended diet continues to find support: Truswell,61 citing a cohort study reporting that the risk of CHD in women was lowest on the top quintile of intake of poly-unsaturated fat;62 this association was related to high nut consumption. The fat-modified diet has been superseded in most dietary recommendations by a Mediterranean-type dietary pattern in CVD prevention based on epidemiological,8 laboratory and the recent clinical trial evidence. Reduction in intake of saturated fat is common to the fat-modified diet and the Mediterranean regime. One meta-analysis reporting that linoleic acid doubled CVD rates63 is flawed by inclusion of very underpowered trials, in which some required subjects to drink large quantities of seed oils (an intervention of no practicable general application). A trial44 in which the end point was progression/regression of coronary atherosclerosis and not CVD events was included, and the analysis comprised only eight of the many earlier dietary trials; no less than 48 were found eligible in the Cochrane Review cited.6

Implications for preventive strategy For many years, there was a limited acceptance by the medical profession and the public of the importance of serum cholesterol lowering and the effect of diet in reducing

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CVD risk. The first public recommendations of a low-fat or fat-modified diet were in 1959 and 1961,64,65 but controversy persisted both as to the effectiveness and safety of cholesterol lowering for 30 years. In 1994, meta-analyses of the earlier dietary and drug trials established safety and moderate efficacy, the reduction of events showing a direct correlation with the extent of cholesterol lowering.2 In the same year, a review found concerns about the safety of cholesterol lowering to be unjustified.66 More influentially, also in 1994, the first of a series of well-designed powerful controlled trials was reported, attesting to the remarkable effect of statins in safely reducing CVD incidence and mortality.67 This has led to the widespread use of this group of drugs in secondary, and later in primary prevention. Since that time, reduction of serum cholesterol has rapidly become fully accepted clinical practice, first in secondary prevention and soon after in primary prevention of CVD. The availability and success of the statins have also served to reduce attention by the medical profession and the public to the importance of diet. This is regrettable: as the Western diet, with high intakes of energy, saturated fat, refined carbohydrate and sodium, and limited consumption of fruit, vegetables and unrefined cereals, is a central cause of CVD, improved nutrition is a fundamental approach to prevention. Statin treatment is clearly effective and with appropriate use may be cost-effective;68 yet it neither addresses the prevalent risk factors of obesity nor the main features of the metabolic syndrome. The frequent minor side effects of statins,69 notably musculoskeletal discomfort and dyspepsia, reduce long-term compliance;70 even their uncommon serious side effects will occur frequently in a scenario of very widespread use in primary prevention. Compliance with an optimal diet will reduce the number of patients requiring medication to achieve appropriate lipid lowering; where medication proves necessary, diet may reduce the dose necessary to do so. The recent trials of the Mediterranean diet provide level 1 evidence for renewed efforts to promote and facilitate population-wide adoption of an improved diet. This will involve an enhanced effort by voluntary bodies and government: education at adult and school levels, effective advertising which will require government funding, even financial measures. The Danish attempt at a ‘fat tax’71 failed because habitual food items were easily bought across national borders; countries such as Australia and New Zealand would be better venues for a trial of this strategy. Subsidy of preferred food items is a further possible approach. The need for participation by government is illustrated by two recently reported instances of resistance by the USA food industry to efforts to reduce consumption of high sucrose drinks72 and high sugar, high saturated fat snacks.73 Lying between edict and voluntarism, a more effective option would be selective taxation and subsidy. There is a close parallel between the successful joint efforts by government and voluntary bodies to reduce cigarette use and the present need to improve public compliance with presentday dietary recommendations.

The actual diets employed in these controlled trials may not be optimal for population use in all cultures on the grounds of food preference, palatability and cost. Nor has the last word been said on the optimal composition of a diet for CVD risk reduction, and further trials may be anticipated. A high intake of extra-virgin olive oil is costly and may not be widely palatable in some populations; a combination of the two principal dietary supplements of the Predimed study may prove more acceptable, together with reduction in saturated fat, sucrose and salt, and increased use of fruit, vegetables, unrefined carbohydrate, fish and white meat. This regime is advocated in recent American Heart Association recommendations.74 Potentially valuable food items that are not prominent in the Mediterranean diet may be included in countries where they are consumed more widely (e.g. tea and green tea are good sources of antioxidants). With the additional feature of moderate restriction of sodium intake, the diet becomes closely similar to the Dietary Approaches to Stop Hypertension diet,75 which has been established in feeding experiments to reduce elevated blood pressure.

Conclusions Recent advances have been made in our understanding of optimal dietary recommendations for the prevention of CVD. These justify renewed and enhanced efforts to maximise public acceptance of a ‘Heart-Healthy diet’. Specifically, current evidence exists to recommend increased regular consumption of fruit and vegetables including legumes, nuts, fish, low-fat dairy products, lean poultry and lean meat; intake of saturated fat should be substantially reduced, and trans-unsaturated fat should be eliminated from manufactured foods.

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© 2013 The Authors International Journal of Evidence-Based Healthcare © 2013 The Joanna Briggs Institute

Thought for food: Clinical evidence for the dietary prevention strategy in cardiovascular disease.

A modified diet has been advocated for the past 50 years for prevention of cardiovascular disease. The evidence has in the past been largely epidemiol...
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